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DOI | 10.1093/toxsci/kfu124 |
Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes | |
Rudraiah, Swetha1; Rohrer, Philip R.1; Gurevich, Igor2; Goedken, Michael J.3; Rasmussen, Theodore1; Hines, Ronald N.4; Manautou, Jose E.1 | |
发表日期 | 2014-09-01 |
ISSN | 1096-6080 |
卷号 | 141期号:1页码:263-277 |
英文摘要 | Acetaminophen (APAP) pretreatment with a hepatotoxic dose (400 mg/kg) in mice results in resistance to a second, higher dose (600 mg/kg) of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in our mouse model of APAP autoprotection. The role of liver Fmo3, which detoxifies xenobiotics, in APAP autoprotection is unknown. The purpose of this study was to characterize the gene regulation and protein expression of liver Fmo3 during APAP hepatotoxicity. The functional consequences of Fmo3 induction were also investigated. Plasma and livers were collected from male C57BL/6J mice over a period of 72 h following a single dose of APAP (400 mg/kg) to measure Fmo3 mRNA and protein expression. Although Fmo3 mRNA levels increased significantly following APAP treatment, protein expression changed marginally. In contrast, both Fmo3 mRNA and protein expression were significantly higher in APAP autoprotected livers. Unlike male C57BL/6J mice, female mice have similar to 80-times higher constitutive Fmo3 mRNA levels and are highly resistant to APAP hepatotoxicity. Coadministration of APAP with the FMO inhibitor methimazole rendered female mice susceptible to APAP hepatotoxicity, with no changes in susceptibility detected in male mice. Furthermore, a human hepatocyte cell line (HC-04) clone over-expressing human FMO3 showed enhanced resistance to APAP cytotoxicity. Taken together, these findings establish for the first time induction of Fmo3 protein expression and function by xenobiotic treatment. Our results also indicate that Fmo3 expression and function plays a role in protecting the liver from APAP-induced toxicity. Although the mechanism(s) of this protection remains to be elucidated, this work describes a novel protective function for this enzyme. |
英文关键词 | acetaminophen;autoprotection;Fmo3;hepatotoxicity;inhibitor;methimazole |
语种 | 英语 |
WOS记录号 | WOS:000342990200030 |
来源期刊 | TOXICOLOGICAL SCIENCES |
来源机构 | 美国环保署 |
文献类型 | 期刊论文 |
条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/59538 |
作者单位 | 1.Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA; 2.Cellular Dynam Int, Madison, WI 53711 USA; 3.Rutgers State Univ, Off Translat Sci, New Brunswick, NJ 08901 USA; 4.US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA |
推荐引用方式 GB/T 7714 | Rudraiah, Swetha,Rohrer, Philip R.,Gurevich, Igor,et al. Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes[J]. 美国环保署,2014,141(1):263-277. |
APA | Rudraiah, Swetha.,Rohrer, Philip R..,Gurevich, Igor.,Goedken, Michael J..,Rasmussen, Theodore.,...&Manautou, Jose E..(2014).Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes.TOXICOLOGICAL SCIENCES,141(1),263-277. |
MLA | Rudraiah, Swetha,et al."Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection Is Associated with Induction of Flavin-Containing Monooxygenase-3 (FMO3) in Hepatocytes".TOXICOLOGICAL SCIENCES 141.1(2014):263-277. |
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